cd19/cd22 bicistronic chimeric antigen receptor (car) t cells in children and young adults with recurrent or refractory cd19/cd22-expressing b cell malignancies

Conditions: B-NHL; B-Non Hodgkin Lymphoma; Acute Lymphocytic Leukemia; Acute Lymphoblastic Leukemia; B-precursor ALL; B-All; Lymphoma, Non-Hodgkin; Leukemia, Lymphocytic, B Cell; B-Cell Lymphoma; B-Cell Leukemia; Acute Lymphoid Leukemia

Summary: background: acute lymphoblastic leukemia (all) is the most common cancer in children. about 90% of children and young adults who are treated for all can now be cured. but if the disease comes back, the survival rate drops to less than 50%. better treatments are needed for all relapses. objective: to test chimeric antigen receptor (car) therapy. cars are genetically modified cells created from each patient s own blood cells. his trial will use a new type of car t-cell that is targeting both cd19 and cd22 at the same time. cd19 and cd22 are proteins found on the surface of most types of all. eligibility: people aged 3 to 39 with all or related b-cell lymphoma that has not been cured by standard therapy. design: participants will be screened. this will include: physical exam blood and urine tests tests of their lung and heart function imaging scans bone marrow biopsy. a large needle will be inserted into the body to draw some tissues from the interior of a bone. lumbar puncture. a needle will be inserted into the lower back to draw fluid from the area around the spinal cord. participants will undergo apheresis. their blood will circulate through a machine that separates blood into different parts. the portion containing t cells will be collected; the remaining cells and fluids will be returned to the body. the t cells will be changed in a laboratory to make them better at fighting cancer cells. participants will receive chemotherapy starting 4 or 5 days before the car treatment. participants will be admitted to the hospital. their own modified t cells will be returned to their body. participants will visit the clinic 2 times a week for 28 days after treatment. follow-up will continue for 15 years....

background: * despite improvements in therapy, acute lymphoblastic leukemia (all) contributes to significant morbidity and mortality for children and young adults with cancer. cd19-car and cd22-car therapy have proven highly effective in inducing remission in patients with relapsed/refractory disease. * immune escape has been observed by several groups following cd19-car and cd22- car therapy for b-all. investigation of this phenomenon reveals a complex biology responsible for loss or downregulation of cd19 and/or cd22 expression observed in these cases. * the challenges encountered with currently available cd19- and cd22-directed car t cells in b-all demonstrates the need for combinatorial treatment strategies simultaneously targeting two antigens, such as cd19 and cd22, to enhance the long-term effectiveness of cars. * we have previously treated patients with b-all on a phase 1/2 clinical trial using a bivalent cd19/22 car t-cell as a first combinatorial treatment strategy. this car t-cell construct is well-tolerated and has yielded responses however there has been limited car t cell expansion and persistence. additionally, the previously tested cd19/cd22 bivalent car t-cell construct is limited in its ability to target cd22. * this new cd19/22 targeted construct being tested in this clinical trial has improved dual targeting capability based on preclinical data/evaluation. objectives: * phase i: assess the safety of administering escalating doses of autologous cd19/cd22- car engineered t cells in children and young adults with b cell all (stratified by disease burden) or lymphoma following a cyclophosphamide/fludarabine conditioning regimen. * phase ii: determine the efficacy of cd19/cd22 therapy in participants stratified by disease burden. eligibility: -participants between \>= 3 years and \<= 39 years of age, with cd19+/cd22+ b cell all or lymphoma who have relapsed or have refractory disease after at least one standard chemotherapy regimen and one salvage regimen, with no alternative curative options. design: * phase i, 3 + 3 dose escalation design across 3 cohorts (b-all/b-cell lymphoblastic lymphoma: a: low-disease burden (\ = 25 % marrow blasts or with emd): c: b-cell non-hodgkin lymphoma using the following dose levels: -2: 1 x 10\^5 transduced t cells/kg (+/- 20%); -1: 3 x 10\^5 transduced t cells/kg (+/- 20%); 1: 1 x 10\^6 transduced t cells/kg (+/- 20%); and 2: 3x 10\^6 transduced t cells/kg (+/- 20%). cohorts will enroll concurrently. * participants will be treated based on disease burden and will receive 1 of 2 lymphodepleting preparative regimens: * lymphodepleting preparative regimen number 1: fludarabine (30 mg/m\^2/d x 3 on days -4, -3, -2) and cyclophosphamide (900 mg/m\^2/d x 1 on day -2) followed by infusion of cd19/cd22-car t-cells on d0. * lymphodepleting preparative regimen #2: fludarabine (30 mg/m2/d x 4 on days -5, -4, -3, -2) and cyclophosphamide (600 mg/m2/d x 2 on days -3, -2) followed by infusion of cd19/cd22-car t-cells on d0. * determination for use of ld regimen #1 versus #2 will be based on pre-treatment absolute lymphocyte count, pre-existing cytopenias, receipt of prior car t-cell therapy, high disease burden and assessment of infection risk. * participants will be evaluated sequentially for toxicity, antitumor effects, car expansion and persistence, and other biologic correlatives.

Eligibility criteria:
* inclusion criteria: * diagnosis * participant must: * have pathology confirmed b cell all (not isolated to the testis or cns), cml with all transformation, or high-grade lymphoma (e.g., burkitt s lymphoma, b-lymphoblastic lymphoma, diffuse large b-cell lymphoma, inclusive of low-grade lymphoma that has transformed to high grade disease); and * have relapsed or been refractory after at least one standard chemotherapy regimen and at least one salvage treatment. participants with philadelphia chromosome + all must have failed prior tyrosine kinase inhibitor; and * be ineligible for allogeneic stem cell transplant (sct), have refused sct, or have recurred after sct; and * have no evidence of graft-versus- host disease (gvhd) and have been without immunosuppressive agents for at least 30 days prior to apheresis, if undergone prior allogeneic sct; and * be unable to access (in a timely manner), ineligible for, or have relapsed/failed after or not responded to a commercially available cd19 car t-cell construct; and * have evidence of at least minimal residual disease or pet-avid disease (lymphoma) at the time of enrollment. * cd22/cd19 expression * cd19 must be detected on \>15% of the malignant cells by immunohistochemistry or \> 80% by flow cytometry. * cd22 positivity must be confirmed. * age \>= 3 years of age and \<=39 years of age at time of enrollment. * clinical performance status: participants \>= 16 years of age: karnofsky \>= 50%; participants \ = 50%. * participants must have adequate organ and marrow function as defined below: * leukocytes \>= 750/mcl\* * platelets \>= 50,000/mcl\* * total bilirubin \ 3x uln) * ast(sgot)/alt(sgpt) \<=10 x institutional upper limit of normal * creatinine \<= the maximum for age listed in the table below or * measured creatinine clearance \>=60 ml/min/1.73 m\^2 for participants with creatinine levels above the max listed below per age. * age (years) \<= 5 \|\| maximum serum creatinine (mg/dl) \<= 0.8 * age (years) 6 to \<= 10 \|\| maximum serum creatinine (mg/dl) \<= 1.0 * age (years) \>10 \|\| maximum serum creatinine (mg/dl) \<= 1.2 * a participant will not be excluded because of pancytopenia \>= grade 3 if it is due to underlying bone marrow involvement by leukemia * central nervous system (cns) status * participants with leukemia with cns 1 and 2 disease are eligible in the absence of exclusion criteria * participants of child-bearing or child-fathering potential must be willing to practice effective birth control from the time of enrollment until 12 months following completion of study treatment for women and for 4 months following completion of study treatment for men. * participants who are breastfeeding or plan to breastfeed must agree to discontinue/postpone breastfeeding while on study therapy and until 1 month after the administration of car. * cardiac function: left ventricular ejection fraction \>= 45% or fractional shortening \>=28% * pulmonary function * baseline oxygen saturation \>92% on room air at rest * ability of participant or legally authorized representative (lar) to understand and the willingness to sign a written informed consent document. * ability and willingness of participant or legally authorized representative (lar) to co- enroll on 15-c-0028: follow-up evaluation for gene-therapy related delayed adverse events after participation in pediatric oncology branch clinical trials. exclusion criteria: participants meeting any of the following criteria are not eligible for participation in the study: * participants with cns3 disease, neurologic signs of cns disease, radiologically detected active cns lymphoma * hyperleukocytosis (\>= 50,000 blasts/microl) * positive serum or urine beta-hcg pregnancy test performed at screening. * participants will be excluded based on prior therapy if they fail to meet following washout criteria: * therapy: systemic chemotherapy, anti-neoplastic agents, antibody- based therapies * washout\*: \>=2 weeks * exceptions: 6 weeks for clofarabine or nitrosoureas; no washout for prior intrathecal chemotherapy, steroid therapy, hydroxyurea (no dose increases within prior 2 weeks) or all maintenance-type chemotherapy (vincristine, 6-mercaptopurine, oral methotrexate, or a tyrosine kinase inhibitor for participants with ph+ all) provided there is recovery from any acute toxic effects * therapy: radiation * washout\*: \>=3 weeks * exceptions: no time restriction with radiation therapy if the volume of bone marrow treated is less than 10% and the participant has measurable/evaluable disease outside the radiation window * therapy: allogeneic stem cell transplant * washout\*: \>= 100 days since sct; \>= 30 days since completion of immunosuppression; \>= 6 weeks since donor lymphocyte infusion (dli) * exceptions: cannot have evidence of active graft-versus-host disease (gvhd) * therapy: car t-cell therapy or other adoptive cell therapy * washout\*: \> 30 days post infusion * washout: time between therapy and apheresis * positive hiv antibodies consistent with active hiv. * positive hepatitis c antibodies or positive hepatitis b surface antigen (hbsag) indicative of current/active hcv/hbv. * active second malignancy other than in situ carcinoma of the cervix, unless the tumor was treated with curative intent at least two years previously and participant is in remission. * history of severe, immediate hypersensitivity reaction attributed to compounds of similar chemical or biologic composition to any agents used in study or in the manufacturing of the cells. * uncontrolled, symptomatic, intercurrent illness or social situations that would limit compliance with study requirements or in the opinion of the pi would pose an unacceptable risk to the participant.

Keywords: philadelphia chromosome + all lymphoma cd-22 expressing tumor cd-19 expressing tumor adoptive immunotherapy b-all b-precursor all acute lymphoblastic leukemia acute lymphocytic leukemia b-non hodgkin lymphoma